Analysis of potential biomarkers for diabetic kidney disease based on single-cell RNA-sequencing integrated with a single-cell sequencing assay for transposase-accessible chromatin.

Diabetic kidney disease (DKD) is a renal microvascular disease caused by hyperglycemia that involves metabolic remodeling, oxidative stress, inflammation, and other factors. The mechanism is complex and not fully unraveled. We performed an integrated single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) and single-cell RNA-sequencing (scRNA-seq) analyses of kidneys from db/db and db/m mice to identify differential open chromatin regions and gene expression, particularly in genes related to proximal tubular reabsorption and secretion. We identified 9,776 differentially expressed genes (DEGs) and 884 cell type-specific transcription factors (TFs) across 15 cell types. Glucose and lipid transporters, and TFs related to the circadian rhythm in the proximal tubules had significantly higher expression in db/db mice than in db/m mice (P<0.01). Crosstalk between podocytes and tubular cells in the proximal tubules was enhanced, and renal inflammation, oxidative stress, and fibrosis pathways were activated in db/db mice. Western blotting and immunohistochemical staining results showed that Wfdc2 expression in the urine and kidneys of DKD patients was higher than that in non-diabetic kidney disease (NDKD) controls. The revealed landscape of chromatin accessibility and transcriptional profiles in db/db mice provide insights into the pathological mechanism of DKD.

Established the first clinical prediction model regarding the risk of hyperuricemia in adult IgA nephropathy.

OBJECTIVE: To construct a novel nomogram model that predicts the risk of hyperuricemia incidence in IgA nephropathy (IgAN). METHODS: Demographic and clinicopathological characteristics of 1184 IgAN patients in the First Affiliated Hospital of Zhengzhou University Hospital were collected. Univariate analysis and multivariate logistic regression were used to screen out hyperuricemia risk factors. The risk factors were used to establish a predictive nomogram model. The performance of the nomogram model was evaluated using an area under the receiver-operating characteristic curve (AUC), calibration plots, and a decision curve analysis. RESULTS: Independent predictors for hyperuricemia incidence risk included sex, hypoalbuminemia, hypertriglyceridemia, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), 24 h urinary protein (24 h TP), gross hematuria and tubular atrophy/interstitial fibrosis (T). The nomogram model exhibited moderate prediction ability with an AUC of 0.834 (95% CI 0.804-0.864). The AUC from validation reached 0.787 (95% CI 0.736-0.839). The decision curve analysis displayed that the hyperuricemia risk nomogram was clinically applicable. CONCLUSION: Our novel and simple nomogram containing 8 factors may be useful in predicting hyperuricemia incidence risk in IgAN.

IgA nephropathy with acute kidney disease: Characteristics, prognosis, and causes.

BACKGROUND: The clinical manifestations and prognosis of IgA nephropathy (IgAN) are diverse. Some patients may present with kidney dysfunction lasting shorter than 3 months and meet the acute kidney disease (AKD) criteria. This study aimed to investigate the clinicopathological features, causes and prognosis of newly diagnosed cases of IgAN with AKD. METHODS: 1320 IgAN patients diagnosed via kidney biopsy between January 2012 and June 2018 were included in this retrospective study, with a median follow-up period of 35 months. We analyzed the clinicopathological, etiological variables, as well as short-term and long-term prognosis. The main outcome was a composite event of 40% decline in eGFR, kidney failure or death. RESULTS: Incidence of AKD was 8.8% in the newly diagnosed IgAN patients, and was found to be an independent risk factor affecting the short-term (HR, 7.1; 95% CI, 2.3-22.2; P = 0.001) and long-term (HR, 1.8; 95% CI, 1.2-2.6; P = 0.006) prognosis, respectively. The most common cause of AKD was malignant hypertension-related AKD (MHT-AKD; 24.1%), followed by hematuria-related AKD (H-AKD; 12.9%), nephrotoxic-drug-exposure-related AKD (NTDE-AKD; 12.1%) and crescents-related AKD (C-AKD; 11.2%). The patients in AKD group had more severe clinicopathological characteristics and poor short-term and long-term prognosis than non-AKD group. In subgroup analysis, the MHT-AKD had the worst 5 years survival rate, followed by NTDE-AKD and C-AKD, whereas H-AKD had the best survival rate. CONCLUSIONS: AKD is not rare among IgAN patients, and is an independent risk factor for short-term and long-term prognosis. IgAN patients with AKD resulting from different causes have different prognosis.

Hyperuricemia aggravates the progression of IgA nephropathy.

OBJECTIVE: The relationship between hyperuricemia and IgA nephropathy (IgAN) was evaluated systematically in this research. METHODS: The Preferred Reporting Items for Systematic Review and Meta-analysis statement was employed to design and report the study. RESULTS: Twenty-five studies were included in this meta-analysis with a total of 6048 IgAN patients. The clinical indicators indicated that blood urea nitrogen (BUN) (p < 0.00001, mean difference (MD) = 2.60, 95% confidence interval (CI) 1.74-3.46), serum creatinine (Scr) (p < 0.00001, MD = 44.56, 95% CI 31.15-57.98), diastolic blood pressure(DBP) (p < 0.00001, MD = 3.86, 95% CI 2.84-4.88), systolic blood pressure(SBP) (p < 0.00001, MD = 6.71, 95% CI 4.70-8.71), and 24-h urine protein(24 h TP) (p < 0.00001, MD = 0.76, 95% CI 0.58-0.94) were significantly increased in IgAN with hyperuricemia group than that in normouricemic IgAN group. The pathological analysis indicated that mesangial proliferation (p < 0.00001, MD = 0.12, 95% CI 0.07-0.17), vascular lesion (p < 0.00001, MD = 0.17, 95% CI 0.13-0.20), segmental lesion (p < 0.00001, MD = 0.15, 95% CI 0.03-0.26), tubulointerstitial damage (p < 0.00001, MD = 1.27, 95% CI 1.06-1.48), and glomerulosclerosis (p < 0.00001, MD = 0.56, 95% CI 0.40-0.72) were considerably climbed in IgAN patients with hyperuricemia compared without hyperuricemia group. Additionally, the estimated glomerular filtration rate (p < 0.00001, MD = - 29.03, 95% CI - 36.83 to - 21.23) was decreased in IgAN patients with hyperuricemia compared with normouricemic group. CONCLUSION: Hyperuricemia exacerbates IgAN prognosis through aggravating the clinical outcomes and pathological results of IgAN.

miR-374a Regulates Inflammatory Response in Diabetic Nephropathy by Targeting MCP-1 Expression.

The microRNA (mir)-374a has been implicated in several types of human cancer; however, its role in diabetic nephropathy (DN) remains unclear. Monocyte chemoattractant protein (MCP)-1 is a chemokine that recruits macrophages to inflammatory sites and is important for the development and progression of DN. However, the relationship between miR-374a and MCP-1 in DN is unknown. We addressed this in the present study by examining the expression of these factors in kidney tissue samples from DN patients and through loss- and gain-of-function experiments using HK2 human renal tubular epithelial cells. We found that miR-374a was downregulated whereas MCP-1 was upregulated in DN tissue. A bioinformatics analysis revealed that MCP-1 is a putative target of miR-374a. To confirm this relationship, HK2 cells treated with normal glucose (5.6 mmol/l D-glucose), high glucose (HG) (30 mmol/l D-glucose), or high osmotic pressure solution (5.6 mmol/l D-glucose + 24.4 mmol/l D-mannitol) were transfected with miR-374a mimic or inhibitor. miR-374a mimic reduced MCP-1 mRNA expression and migration of co-cultured U937 cells, whereas miR-374a inhibition had the opposite effects. Additionally, interleukin-6 and -18 and tumor necrosis factor-α levels were downregulated by transfection of miR-374a mimic. On the other hand, MCP-1 overexpression reversed the inhibitory effects of miR-374a in HK2 cells. Thus, miR-374a suppresses the inflammatory response in DN through negative regulation of MCP-1 expression. These findings suggest that therapeutic strategies that target the miR-374a/MCP-1 axis can be an effective treatment for DN.